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The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts specifically to foreign invaders. The thymus is composed of two identical lobes and is located anatomically in the anterior superior mediastinum, in front of the heart and behind the sternum. Microscopically, each lobe of the thymus can be divided into a central medulla and a peripheral cortex which is surrounded by an outer capsule. The cortex and medulla play different roles in the development of T cells. Cells in the thymus can be divided into thymic stromal cells and cells of hematopoietic origin (derived from bone marrow resident hematopoietic stem cells). Developing T cells are referred to as thymocytes and are of hematopoietic origin. Stromal cells include epithelial cells of the thymic cortex and medulla, and dendritic cells.

Thymus
Illu thymus.jpg
Thymus
Details
PrecursorOf the epithelium - third pharyngeal arch
SystemLymphatic system, part of the immune system
Lymphtracheobronchial, parasternal
FunctionSupport the development of functional T cells
Identifiers
LatinThymus
MeSHD013950
TAA13.1.02.001
FMA9607
Anatomical terminology

The thymus provides an environment for development of T cells from precursor cells. The cells of the thymus provide for development of T cells that are functional and self-tolerant. Therefore, one of the most important roles of the thymus is the induction of central tolerance.

The thymus is largest and most active during the neonatal and pre-adolescent periods. By the early teens, the thymus begins to decrease in size and activity and the tissue of the thymus is gradually replaced by adipose (fat) tissue. Nevertheless, residual T lymphopoiesis continues throughout adult life.

StructureEdit

In children, the thymus is pinkish-gray, soft, and lobulated on its surfaces.[1] At birth it is about 4–6 cm long, 2.5–5 cm wide, and about 1 cm thick.[2] It increases in size until puberty, where it may have a size of about 40 g, following which it decreases in size in a process known as involution.[3] It is made up of two lobes that meet in upper midline, that stretch from below the thyroid in the neck to as low as the cartilage of the fourth rib.[1] It lies beneath the sternum, rests on the pericardium, and is separated from the aortic arch and great vessels by a layer of fascia. The left brachiocephalic vein may even be embedded within the thymus.[1] In the neck, it lies on the front and sides of the trachea, behind the sternohyoidei and sternothyreoidei.[1]

MicroanatomyEdit

The thymus consists of two lobes, merged in the middle, surrounded by a capsule that extends with blood vessels into the interior.[2] The lobes consist of an outer cortex rich with cells and an inner less dense medulla.[3] The lobes are divided into smaller lobules 0.5-2mm diameter, between which extrude radiating insertions from the capsule along septa.[1]

The cortex is mainly made up of thymocytes, supported by a network of finely-branched epithelial reticular cells, which is continuous with a similar network in the medulla. This network forms an adventitia to the blood vessels, which enter the cortex via septa near the junction with the medulla.[1]

In the medulla, the network of reticular cells is coarser than in the cortex, the lymphoid cells are relatively fewer in number, and there are concentric, nest-like bodies called Hassall's corpuscles. These are concentric, layered whorls of epithelial cells that increase in number throughout life.[1] They are the remains of the epithelial tubes, which grow out from the third pharyngeal pouches of the embryo to form the thymus.[4] In the center of the medullary portion there are very few vessels, and they are of minute size.


Blood and nerve supplyEdit

The arteries supplying the thymus are branches of the internal thoracic, and inferior thyroid arteries, with branches from the superior thyroid artery sometimes seen.[2] The branches reach the thymus and travel with the septa of the capsule into the area between the cortex and medulla, where they enter the thymus itself; or alternatively directly enter the capsule.[2]

The veins of the thymus end in the left brachiocephalic vein, internal thoracic vein, and in the inferior thyroid veins.[2] Sometimes the veins end directly in the superior vena cava.[2]

Lymphatic vessels travel only away from the thymus, accompanying the arteries and veins. These drain into the brachiocephalic, tracheobronchial and parasternal lymph nodes.[2]

The nerves supplying the thymus arise from the vagus nerve and the cervical sympathetic chain. Branches from the phrenic nerves reach the investing capsule, but do not enter into the thymus itself. Although present, the exact role of the nerve supply of the thymus is little understood.[1]

VariationEdit

The two lobes differ slightly in size and may be united or separated.[5] Thymic tissue may be found scattered on or around the gland.[1]

DevelopmentEdit

 
Scheme showing development of branchial epithelial bodies from the thoracic cavity of the foetus. I, II, III, IV. Branchial pouches.

The thymocytes and the epithelium of the thymus have different developmental origins.[3] The epithelium of the thymus develops first, appearing as two outgrowths, one on either side, of the third pharyngeal pouch.[3] These extend outward and backward into the surrounding mesoderm and neural crest-derived mesenchyme in front of the ventral aorta. Here the thymocytes and epithelium meet and join with connective tissue. The pharyngeal opening of each diverticulum is soon obliterated, but the neck of the flask persists for some time as a cellular cord. By further proliferation of the cells lining the flask, buds of cells are formed, which become surrounded and isolated by the invading mesoderm. Additional portions of thymus tissue are sometimes developed from the fourth pharyngeal pouch.[6]

The epithelium forms fine lobules, and develops into a sponge-like structure. During this stage, hematopoietic bone-marrow precursors migrate into the thymus.[3] Normal development is dependent on the interaction between the epithelium and the hematopoietic thymocytes. Iodine is also necessary for thymus development and activity.[7]

InvolutionEdit

The thymus continues to grow after the birth reaching the maximum size by the end of the first year of life. It is most active in fetal and neonatal life.[8] It then begins to decrease in size and activity in a process called thymic involution.[3] After the first year of life the amount of lymphocytes begins to fall.[3] The thymic peri-vascular space grows proportionally in volume while the true thymic epithelial space decreases in size. In addition the connective tissue fills a part of the thymic volume.[9] During involution, the thymus decreases in size and activity.[3] Fat cells are present at birth, but increase in size and number markedly after puberty, invading the gland from the walls between the lobules first, then into the cortex and medulla.[3] This process continues into old age, where whether with a microscope or with the human eye, the thymus may be difficult to detect.[3]

The atrophy is due to the increased circulating level of sex hormones, and chemical or physical castration of an adult results in the thymus increasing in size and activity.[10]

FunctionEdit

T cells, an important part of the immune system that affects cell-mediated immunity, mature in the thymus.[11] T cells begin as hematopoietic precursors from the bone-marrow, referred to as thymocytes, where they migrate to the thymus. Here, they undergo a process of maturation, which involves ensuring the cells react against antigens, but that they do not react against antigens found on body tissue.[11] Once mature, T cells emigrate from the thymus.[11]

The cortex is the location of the earliest events in thymocyte development, where T-cell receptor gene rearrangement and positive selection takes place. The medulla is the location of the latter events in thymocyte development. Thymocytes that reach the medulla have already successfully undergone T-cell receptor gene rearrangement and positive selection, and have been exposed to a limited degree of negative selection. The medulla is specialized to allow thymocytes to undergo additional rounds of negative selection to remove auto-reactive T cells from the mature repertoire. Transcriptional regulators AIRE and FEZ2 are expressed by the thymic medullary epithelium, and drives the transcription of organ-specific genes such as insulin to allow maturing thymocytes to be exposed to a more complex set of self-antigens than is present in the cortex.

Each T cell attacks a specific substance which it identifies with its receptor. T cells have receptors which are generated by randomly shuffling gene segments. Each T cell attacks a different antigen. T cells that attack the body's own proteins are eliminated in the thymus. Thymic epithelial cells express major proteins from elsewhere in the body. First, T cells undergo "Positive Selection", whereby the cell comes in contact with self-MHC, expressed by thymic epithelial cells; those with no interaction die by a lack of stimulatory signal. Second, the T cell undergoes "Negative Selection" by interacting with thymic dendritic cells, whereby T cells with a strong interaction with self-MHC and/or self-antigen die by induced apoptosis or are induced to become a regulatory T cell, to avoid autoimmunity. Those with intermediate affinity survive.

The stock of T-lymphocytes is built up in early life, so the function of the thymus is diminished in adults. It is largely degenerated in elderly adults and is barely identifiable, consisting mostly of fatty tissue. Involution of the thymus has been linked to loss of immune function in the elderly, susceptibility to infection and to cancer.

The ability of T cells to recognize foreign antigens is mediated by the T-cell receptor. The T-cell receptor undergoes genetic rearrangement during thymocyte maturation, resulting in each T cell bearing a unique T-cell receptor, specific to a limited set of peptide:MHC combinations. The random nature of the genetic rearrangement results in a requirement of central tolerance mechanisms to remove or inactivate those T cells which bear a T-cell receptor with the ability to recognise self-peptides.

  1. A rare population of hematopoietic progenitor cells enter the thymus from the blood, and expands by cell division to generate a large population of immature thymocytes.[12]
  2. Immature thymocytes each make distinct T-cell receptors by a process of gene rearrangement. This process is error-prone, and some thymocytes fail to make functional T-cell receptors, whereas other thymocytes make T-cell receptors that are autoreactive.[13]
  3. Immature thymocytes undergo a process of selection, based on the specificity of their T-cell receptors. This involves selection of T cells that are functional (positive selection), and elimination of T cells that are autoreactive (negative selection). The medulla of the thymus is the site of T Cell maturation.
type: functional (positive selection) autoreactive (negative selection)
location: cortex medulla
 

In order to be positively-selected, thymocytes will have to interact with several cell surface molecules, MHC/HLA, to ensure reactivity and specificity.[14]

Positive selection eliminates (by apoptosis) weakly-binding cells and only takes strongly- or medium-binding cells. (Binding refers to the ability of the T-cell receptors to bind to either MHC class I/II or peptide molecules.)

Negative selection is not 100% complete. Some autoreactive T cells escape thymic censorship, and are released into the circulation.

Additional mechanisms of tolerance active in the periphery exist to silence these cells such as anergy, deletion, and regulatory T cells.

If these peripheral tolerance mechanisms also fail, autoimmunity may arise.

Cells that pass both levels of selection are released into the bloodstream to perform vital immune functions.

The thymus also secretes hormones and cytokines that regulate the maturation of T cells, including thymulin, thymopoietin, and thymosins.[3]

Clinical significanceEdit

The immune system is a multicomponent interactive system. It effectively protects the host from various infections. An improperly functioning immune system can cause discomfort, disease or even death. The type of malfunction falls into one or more of the following major groups: hypersensitivity or allergy, auto-immune disease, or immunodeficiency.

HypersensitivityEdit

Allergy results from an inappropriate and excessive immune response to common antigens. Substances that trigger an allergic response are called allergens. Allergies involve mainly IgE, antibodies, and histamine. Mast cells release the histamine. Sometimes an allergen may cause a sudden and severe, possibly fatal reaction in a sensitive individual; this is called anaphylaxis.

ImmunodeficiencyEdit

As the thymus is the organ of T-cell development, any congenital defect in thymic genesis or a defect in thymocyte development can lead to a profound T cell deficiency in primary immunodeficiency disease.[8] Loss of the thymus at an early age through genetic mutation (as in DiGeorge Syndrome) results in severe immunodeficiency and subsequent high susceptibility to infection by viruses, protozoa, and fungi.[15][16] Defects that affect both the T cell and B cell lymphocyte lineages result in severe combined immunodeficiency (SCID).

Examples include:

In mice, the nude mouse strain are congenitally thymic deficient. These mice are an important model of primary T cell deficiency.

Autoimmune diseaseEdit

Autoimmune diseases are caused by a hyperactive immune system that instead of attacking pathogens reacts against the host organism (self) causing disease. One of the primary functions of the thymus is to prevent autoimmunity through the process of central tolerance, immunologic tolerance to self antigens.

APECEDEdit

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an extremely rare genetic autoimmune syndrome. However, this disease highlights the importance of the thymus in prevention of autoimmunity. This disease is caused by mutations in the Autoimmune Regulator (AIRE) gene.[17] AIRE allows for the ectopic expression of tissue-specific proteins in the thymus medulla, such as proteins that would normally only be expressed in the eye or pancreas. This expression in the thymus, allows for the deletion of autoreactive thymocytes by exposing them to self-antigens during their development, a mechanism of central tolerance. Patients with APECED develop an autoimmune disease that affects multiple endocrine tissues.

Thymoma-associated multiorgan autoimmunity (TAMA)Edit

A GVHD-like disease called thymoma-associated multiorgan autoimmunity (TAMA) can occur in patients with thymoma. In these patients rather than a donor being a source of pathogenic T cells, the patient's own malignant thymus produces self-directed T cells. This is because the malignant thymus is incapable of appropriately educating developing thymocytes to eliminate self-reactive T cells. The end result is a disease virtually indistinguishable from GVHD.[18]

Myasthenia gravisEdit

Myasthenia gravis is an autoimmune disease caused by antibodies that block acetylcholine receptors. Myasthenia gravis is often associated with thymic hyperplasia. Thymectomy may be necessary to treat the disease.

Patients with the autoimmune disease myasthenia gravis commonly (70%) are found to have thymic hyperplasia or malignancy.[19]

CancerEdit

Two primary forms of tumours originate in the thymus.

ThymomasEdit

Tumours originating from the thymic epithelial cells are called thymomas, and are found in about 10-15% of patients with myasthenia gravis.[20] Symptoms are sometimes confused with bronchitis or a strong cough because the tumour presses on the recurrent laryngeal nerve. All thymomas are potentially cancerous, but they can vary a great deal. Some grow very slowly. Others grow rapidly and can spread to surrounding tissues. Treatment of thymomas often requires surgery to remove the entire thymus.

LymphomasEdit

Tumours originating from the thymocytes are called thymic lymphomas.[20] Lymphomas or leukemias of thymocyte origin are classified as Precursor T acute lymphoblastic leukemia/lymphoma (T-ALL).

People with an enlarged thymus, particularly children, were treated with intense radiation in the years before 1950. There is an elevated incidence of thyroid cancer and leukemia in treated individuals.[21]

Cervical thymic cystEdit

Cervical thymus is a rare malformation. Thymic tissue containing cysts is rarely described in the literature, ectopic glandular tissue included in the wall of cystic formation can trigger a series of problems similar to those of thymomas.[22]

Thymic cysts are uncommon lesions, about 150 cases being found. While thymic cyst and ectopic cervical thymus are identified most frequently in childhood, the mean age at which thymoma is diagnosed is 45 years. However, studies have shown the existence of necrotic thymic tissue masses in the neck (asymptomatic intravital) more frequently, the incidence reaching nearly 30%. These observations may mean absence of clinical observation.[22]

Surgical removalEdit

Thymectomy is the surgical removal of the thymus. The usual reason for a thymectomy is to gain access to the heart for surgery to correct congenital heart defects in the neonatal period. In neonates, but not older children or adults, the relative size of the thymus obstructs surgical access to the heart. Removal of the thymus in infancy results in immunodeficiency by some measures, although T cells develop compensating function and it remains unknown whether disease incidence in later life is significantly greater.[23][24][25][26] This is because sufficient T cells are generated during fetal life prior to birth. These T cells are long-lived and can proliferate by homeostatic proliferation throughout the lifetime of the patient. However, there is evidence of premature immune aging in patients thymectomized during early childhood.[27]

Other indications for thymectomy include the removal of thymomas and the treatment of myasthenia gravis. Thymectomy is not indicated for the treatment of primary thymic lymphomas. However, a thymic biopsy may be necessary to make the pathologic diagnosis.[27]

ResearchEdit

Thymus transplantationEdit

A thymus may be transplanted, however, this approach is problematic due to donor requirements and matching tissue with the patient.

Thymus tissue engineeringEdit

A fully functional thymus derived from reprogrammed mouse embryonic fibroblasts has been grown in the kidney capsule of mice. The newly formed organ resembled a normal thymus histologically and molecularly, and upon transplantation it was able to restore immune function in immunocompromised mice. The mouse embryonic fibroblasts were reprogrammed into thymic epithelial cells (TECs) by enforcing the expression of one transcription factor, FOXN1.[28][29]

Society and cultureEdit

When used as food for humans, animal thymic tissue is known as (one of the kinds of) sweetbread.

HistoryEdit

The thymus was known to the ancient Greeks, and its name comes from the Greek word θυμός (thumos), meaning "anger",[30] or "heart, soul, desire, life", possibly because of its location in the chest, near where emotions are subjectively felt; or else the name comes from the herb thyme (also in Greek θύμος or θυμάρι), which became the name for a "warty excrescence", possibly due to its resemblance to a bunch of thyme.[31][32]

Galen was the first to note that the size of the organ changed over the duration of a person's life.[33]

In the nineteenth century, a condition was identified as status thymicolymphaticus defined by an increase in lymphoid tissue and an enlarged thymus. It was thought to be a cause of sudden infant death syndrome but is now an obsolete term.[34][35]

Due to the large numbers of apoptotic lymphocytes, the thymus was originally dismissed as a "lymphocyte graveyard", without functional importance. The importance of the thymus in the immune system was discovered in 1961 by Jacques Miller, by surgically removing the thymus from one day old mice, and observing the subsequent deficiency in a lymphocyte population, subsequently named T cells after the organ of their origin.[36][37] Recently, advances in immunology have allowed the function of the thymus in T-cell maturation to be more fully understood.[38]

Other animalsEdit

 
A sheep thymus, several times enlarged, in Peste des petits ruminants

The thymus is present in all jawed vertebrates, where it undergoes the same shrinkage with age and plays the same immunological function as in human beings. Recently, a discrete thymus-like lympho-epithelial structure, termed the thymoid, was discovered in the gills of larval lampreys.[39] Hagfish possess a protothymus associated with the pharyngeal velar muscles, which is responsible for a variety of immune responses.[40] Little is known about the immune mechanisms of tunicates[41] or of Amphioxus.

The thymus is also present in most vertebrates, with similar structure and function as the human thymus. Some animals have multiple secondary (smaller) thymi in the neck; this phenomenon has been reported for mice[42] and also occurs in 5 out of 6 human fetuses.[43] As in humans, the guinea pig's thymus naturally atrophies as the animal reaches adulthood, but the athymic hairless guinea pig (which arose from a spontaneous laboratory mutation) possesses no thymic tissue whatsoever, and the organ cavity is replaced with cystic spaces.

Additional imagesEdit

ReferencesEdit

This article incorporates text in the public domain from page 1273 of the 20th edition of Gray's Anatomy (1918)

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Books
  • Ralston, Stuart H.; Penman, Ian D.; Strachan, Mark W.; Hobson, Richard P. (eds.) (2018). Davidson's principles and practice of medicine (23rd ed.). Elsevier. ISBN 978-0-7020-7028-0.CS1 maint: extra text: authors list (link)

External linksEdit